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Treatment of actinic keratosis

Treatment of actinic keratosis
Author:
Brian Berman, MD, PhD
Section Editors:
Robert P Dellavalle, MD, PhD, MSPH
June K Robinson, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Feb 2023. | This topic last updated: Feb 23, 2023.

INTRODUCTION — Actinic keratoses (AKs), or solar keratoses, are keratotic or scaling macules, papules, or plaques resulting from the intraepidermal proliferation of atypical keratinocytes in response to prolonged exposure to ultraviolet radiation. Although most AKs do not progress to squamous cell carcinoma (SCC), AKs are a concern because the majority of cutaneous squamous cell carcinomas (cSCCs) arise from pre-existing AKs, and AKs that will progress to SCC cannot be distinguished from AKs that will spontaneously resolve or persist [1,2]. Because of these factors, most clinicians routinely treat AKs [3]. Improvement in associated symptoms and cosmetic appearance can be additional benefits of treatment.

The treatment of AKs will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of AKs are discussed separately. (See "Epidemiology, natural history, and diagnosis of actinic keratosis".)

CHOICE OF THERAPY — There are multiple effective treatment options for actinic keratosis (AK), including destructive therapies (eg, cryosurgery, surgery, dermabrasion, photodynamic therapy [PDT]), topical medications (eg, topical fluorouracil, imiquimod, topical tirbanibulin, diclofenac), and field ablation treatments (eg, chemical peels, laser resurfacing). The choice of therapy is influenced by several factors, including:

●Number and distribution of lesions

●Lesion characteristics

●Patient preference (eg, office-based versus home-administered therapy, duration of therapy)

●Patient tolerance for side effects (eg, pain, inflammation, hypopigmentation, scarring)

●Treatment availability and cost

Our approach is based on the above considerations and is consistent with current international and national guidelines (algorithm 1) [4-8]. In general, lesion-directed treatments, such as cryosurgery and surgical procedures, are the primary approach for isolated lesions [3]. Field-directed therapies, such as topical fluorouracil, imiquimod, tirbanibulin, and PDT, are particularly useful for treating areas with multiple AKs.

ONE OR FEW DISCRETE LESIONS

Liquid nitrogen cryosurgery — We suggest liquid nitrogen cryosurgery as first-line therapy for patients with one or a few (two to three or more, depending on the patient's tolerance of treatment) isolated actinic keratoses (AKs) (algorithm 1). Cryosurgery can be quickly performed in an office-based setting, does not require local anesthesia, is inexpensive, is well tolerated by patients, and, in most cases, results in good or excellent cosmetic outcome [9]. However, since this procedure does not produce a specimen for histologic confirmation, it should only be performed when the clinical diagnosis of AK is relatively certain. If there is doubt about the diagnosis, a biopsy for histologic confirmation is warranted:

●Administration – The treatment is delivered by either spray or contact with a cryoprobe. The contact technique is particularly useful for treating small lesions in sensitive areas of the face (eg, periocular, perioral). The freezing time varies from 5 to 10 seconds or more, depending upon lesion size and thickness, with the "ice ball" extending at least 1 mm beyond the clinical margin of the lesion. A single freeze-thaw cycle is adequate for thin lesions, while a double freeze-thaw cycle is required for thicker lesions [10]. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

●Adverse effects and contraindications – Cryosurgery is associated with transient discomfort. Localized edema and the formation of a serohemorrhagic blister develop 12 to 36 hours following the procedure. Healing can result in hypopigmentation.

Cryosurgery is contraindicated for lesions that need pathologic examination to exclude malignancy and in patients with cold urticaria or cryoglobulinemia. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

●Efficacy – The efficacy of liquid nitrogen cryosurgery has been evaluated in a limited number of randomized trials:

•In a 2019 systematic review of eight randomized trials of cryosurgery combined with other topical treatments (ie, imiquimod, topical fluorouracil, ingenol mebutate, diclofenac) versus cryosurgery alone, the response rate for cryosurgery alone ranged from 39 to 76 percent compared with 73 to 89 percent for combination therapy [11]. The included studies were heterogeneous and generally of low methodologic quality.

•Similar clearance rates for cryosurgery, ranging from 40 to 88 percent at three to six months, were reported in randomized trials comparing cryosurgery with other treatment modalities [12-19].

The wide variability in the reported clearance rates may be related to differences across studies in cryosurgery administration, such as freeze time, number of freeze-thaw cycles, use of contact versus spray technique, and distance from the spray tip to the AK [20,21].

Other destructive therapies — Shave excision and curettage, with or without electrodesiccation, and laser ablation with carbon dioxide (CO2) or erbium:yttrium aluminum garnet (Er:YAG) lasers can be used for the treatment of isolated, hyperkeratotic AK lesions. None of these therapies has been evaluated in clinical trials, and their use is based upon limited evidence from small, observational studies and clinical experience. (See 'Hypertrophic/hyperkeratotic lesions' below.)

HYPERTROPHIC/HYPERKERATOTIC LESIONS

Initial treatment — We suggest liquid nitrogen cryosurgery as the initial treatment for hypertrophic or hyperkeratotic lesions (picture 1 and algorithm 1). Because thick lesions are more resistant to liquid nitrogen, freezing times >10 seconds or repeat applications may be necessary. We typically use two freeze-thaw cycles of 10 to 20 seconds, allowing time for the lesion's peripheral rim to thaw. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

For thick lesions that do not respond to liquid nitrogen cryosurgery, shave removal followed by electrodesiccation or cryosurgery to ensure hemostasis may be used as alternative treatment modalities. Lesion specimens should be sent for histopathologic examination to exclude squamous cell carcinoma (SCC). Of note, tissue specimens obtained by shave excision are usually not adequate to determine whether a lesion is invasive or intraepidermal. (See 'When to biopsy' below.)

When to biopsy — A skin biopsy that samples both the epidermis and dermis (eg, deep shave, punch, or incisional biopsy) for histopathologic examination to exclude or confirm the presence of in situ or invasive SCC should be performed in the following circumstances [22] (see "Skin biopsy techniques"):

●Lesions that appear indurated (a finding that suggests the possibility of SCC)

●Painful, ulcerated, or bleeding lesions

●Hyperkeratotic or hypertrophic actinic keratoses (AKs) that failed to resolve after standard therapies or recurred rapidly (<3 months)

A low threshold for considering the possibility of SCC is particularly important in patients who are immunocompromised, since these patients are more likely to have biologically aggressive lesions.

MULTIPLE THIN LESIONS/FIELD CANCERIZATION — Patients with actinic keratosis (AK) often present with multiple lesions and evidence of chronic actinic damage in adjacent areas. This presentation is commonly referred to as "field cancerization." Sun damage indicative of field cancerization is clinically identified by at least two of the following signs: telangiectasia, atrophy, dyspigmentation, and sand paper-like texture [23,24].

Patients with multiple AKs and clinical evidence of field cancerization have an increased risk of developing a cutaneous squamous cell carcinoma (cSCC). They are best treated with so-called "field-directed therapies," which include topical fluorouracil, imiquimod, and photodynamic therapy (PDT), or field-directed treatment in combination with lesion-directed treatment (sequential treatment) (algorithm 1) [25].

First-line therapies

Topical fluorouracil — For patients with multiple thin lesions on the face or scalp, we suggest field treatment with topical fluorouracil cream as a first-line therapy (algorithm 1) [8,26]. Patients with multiple AKs who also have hypertrophic or hyperkeratotic lesions (picture 1) may benefit from the sequential use of lesion-directed and field-directed therapies. (See 'Sequential therapies' below.)

Topical fluorouracil is available in the United States in concentrations of 0.5% and 5%; 1% and 4% concentrations may be available in other countries. We typically use 5% topical fluorouracil cream.

Lower concentration preparations may be associated with better adherence to treatment because of a lower potential for local irritation [27]. In Europe and Canada, a combination fluorouracil-salicylic acid topical solution (0.5% fluorouracil in 10% salicylic acid) is also available:

●Administration – Fluorouracil cream is applied once or twice daily for two to four weeks until superficial erosion occurs. Treatment courses of one, two, and four weeks have demonstrated superiority over placebo for the clearance of AKs, with the four-week course demonstrating the greatest benefit [28].

●Adverse effects – Applied to AK lesions, fluorouracil cream causes inflammation and lesion necrosis (picture 2). Inflammation typically subsides approximately two weeks after topical fluorouracil is discontinued. It typically takes four to six weeks (two to four weeks of which are active treatment) for the skin to progress through erythema, blistering, necrosis with erosion, and re-epithelialization. In patients with extensive AK, the treated area may become extremely inflamed. Thus, pretreatment patient information and education must be thorough to ensure adherence to treatment.

●Efficacy – Multiple randomized trials and meta-analyses have documented the efficacy of topical fluorouracil alone or in combination with other topical agents for the treatment of AK [4,29-31]. Treatment with topical fluorouracil may also be effective for the long-term control of AKs (see 'Long-term control and chemoprevention' below):

•Topical fluorouracil 5% as monotherapy:

-A 2019 multicenter, randomized trial compared the efficacy of 5% fluorouracil cream (twice daily for four weeks), 5% imiquimod cream (once daily, three times per week for four weeks), methyl aminolevulinate (MAL)-PDT, and 0.015% ingenol mebutate gel (once daily for three consecutive days) in 624 patients with AK lesions of any grade [26]. At 12 months, the cumulative probability of treatment success (≥75 percent reduction in the number of AKs counted at baseline) for fluorouracil was 74.7 percent (95% CI 66.8-81.0). For imiquimod, MAL-PDT, and ingenol mebutate, these percentages were 53.9 percent (95% CI 45.4-61.6), 37.7 percent (95% CI 30.0-45.3), and 28.9 percent (95% CI 21.8-36.3), respectively. The rates of adverse events, including erythema, edema, erosions, blisters, scabbing, crusting, and pain, were similar in all treatment groups. A cost-effectiveness evaluation performed on data from this trial showed that topical fluorouracil treatment was more effective and less expensive compared with other therapies 12 months post-treatment [32].

-A previous network meta-analysis evaluating the relative efficacy of PDT and several topical therapies for the outcome of "complete patient clearance" also concluded that topical fluorouracil 5% was the most effective treatment, followed (in order) by topical fluorouracil 0.5%, aminolevulinic acid (ALA)-PDT, imiquimod, ingenol mebutate, MAL-PDT, cryosurgery, topical diclofenac, and placebo [30].

•Topical fluorouracil 0.5% in salicylic acid 10% – In Europe and Canada, a combination fluorouracil-salicylic acid topical solution (0.5% fluorouracil in 10% salicylic acid) is available for the treatment of slightly palpable or moderately thick, hyperkeratotic AK (grade I/II). The efficacy of this combination has been evaluated in a few randomized trials:

-In one trial including 66 patients with an average of eight moderate to severe, hyperkeratotic AKs on the face or scalp, treatment with fluorouracil-salicylic acid topical solution (0.5% fluorouracil in 10% salicylic acid) once daily for six weeks achieved a higher rate of histologic clearance than two cryosurgery treatments administered three weeks apart (62 versus 42 percent) [16]. The recurrence rates of cleared lesions at 14 weeks were 39 percent in the fluorouracil-salicylic acid group and 85 percent in the cryosurgery group. Adverse events, including local erythema, scabbing, and crusting, were more common in the topical fluorouracil-salicylic acid group than in the cryosurgery group (24 versus 6 percent, respectively).

-In another trial, 166 patients with a 25 cm2 area of face or bald scalp with 4 to 10 clinically confirmed AK lesions were treated with fluorouracil-salicylic acid topical solution (0.5% fluorouracil in 10% salicylic acid) or vehicle once daily for 12 weeks. Eight weeks after the end of treatment, more patients achieved complete clinical clearance in the active treatment group than in the vehicle group (69.5 versus 34.6 percent, respectively; odds ratio [OR] 4.9, 95% CI 2.3-10.5) [33]. Adverse effects occurred more frequently in the fluorouracil-salicylic acid group than in the vehicle group and included erythema, pain, inflammation, scab, and erosion.

Topical fluorouracil plus calcipotriol — The addition of calcipotriol (calcipotriene) 0.005% to topical fluorouracil 5% may enhance the efficacy of topical fluorouracil for the treatment of AKs by inducing thymic stromal lymphopoietin expression and influx of CD4+ T cells in the skin [34].

In a small, randomized trial, 131 patients with 4 to 15 AKs within a 25 cm2 area on the face, scalp, or upper extremities were treated with topical fluorouracil 5% plus calcipotriol ointment 0.005% or topical fluorouracil 5% plus vehicle twice daily for four days [34]. At eight weeks, the mean reduction in the number of AKs in all treated areas was greater in patients treated with topical fluorouracil combined with calcipotriol than in patients treated with topical fluorouracil alone (88 versus 26 percent on the face, 76 versus 6 percent on the scalp, 69 versus 10 percent on the right upper extremity, and 79 versus 16 percent on the left upper extremity, respectively). Erythema and burning at the treated areas were more frequent in the combination treatment group than in the topical fluorouracil alone group.

Topical tirbanibulin — Topical tirbanibulin, a synthetic inhibitor of tubulin polymerization and Src kinase signaling, is approved in the United States and Europe for field treatment of AK of the face and scalp [35]. Cost considerations may limit availability in some formularies:

●Administration – Tirbanibulin is applied once daily to up to a 25 cm2 area for five consecutive days.

●Adverse effects – Adverse events include pruritus, pain at the application site, erythema, vesiculation, superficial erosions, and desquamation.

●Efficacy – In two identical, randomized, phase 3 trials, a 25 cm2 contiguous area with four to eight AKs on the face or scalp of 702 adult patients was treated with either topical tirbanibulin 1% ointment or vehicle (placebo) ointment once daily for five consecutive days [36]. In the pooled data of the two trials, at day 57, complete clearance of AK in the treated areas occurred in 49 percent of patients in the tirbanibulin groups and in 9 percent of patients in the vehicle groups (difference, 41 percentage points; 95% CI 35-47). Local skin reactions (including erythema, flaking, or scaling) at the site of application in the two trials were mostly mild and resolved by day 29. Of the patients who had achieved clearance of all AKs in the treated area at day 57, 27 percent maintained complete clearance at one year.

Studies comparing the safety and long-term efficacy of tirbanibulin with those of other available agents for the field treatment of AK are lacking.

Imiquimod — Imiquimod is a topical immune response modifier that can be used as an alternative to topical fluorouracil for the treatment of multiple AKs and field cancerization, although its efficacy is inferior to that of topical fluorouracil. Imiquimod is available as a 5%, 2.5%, and 3.75% cream:

●Administration – Imiquimod 5% cream is typically applied to an involved area of ≤25 cm2 twice weekly for 16 weeks. The cream is applied at night, ideally at least one hour before bedtime, and washed off after eight hours.

Preparations containing 2.5% and 3.75% imiquimod can be used for the treatment of the entire face or the entire scalp. These preparations are applied once daily for two, two-week cycles separated by two weeks of no treatment.

●Adverse effects – Imiquimod stimulates local cytokine induction, resulting in a local, inflammatory reaction characterized by erythema, pruritus, erosion, ulceration, and crusting. Some patients may experience flu-like symptoms, such as fever, chills, myalgia, and malaise. The healing time of lesions treated with imiquimod is approximately two weeks.

●Efficacy – The efficacy of imiquimod for the treatment of AK has been evaluated in several randomized trials and meta-analyses [26,29,31,37]:

•A meta-analysis of five randomized trials including approximately 1300 patients found that treatment with imiquimod 5% cream (two to three times per week for 12 to 16 weeks) resulted in complete resolution of AKs in 50 percent of patients compared with 5 percent with the control vehicle [37].

•In a 2014 network meta-analysis comparing the relative efficacy of several treatments for AK (including three different imiquimod regimens), the absolute complete clearance rate was 63 percent (95% CI 45.5-81.1) for imiquimod 5% for 16 weeks, 56 percent (95% CI 33.8-78.8) for imiquimod 5% for four weeks, and 40 percent (95% CI 15.6-64.2) for imiquimod 3.75% for four weeks [38].

•In a 2019 randomized trial comparing the efficacy of 5% fluorouracil cream, 5% imiquimod cream (once daily, three times per week for four weeks), MAL-PDT, and 0.015% ingenol mebutate gel in 624 patients, treatment success at 12 months for imiquimod (defined as clearance of ≥75 percent of AKs counted at baseline) was 53.9 percent (95% CI 45.4-61.6), which was inferior to that of 5% topical fluorouracil (75 percent) [26].

Photodynamic therapy — Photodynamic therapy (PDT) is an effective therapy for patients with multiple AKs, although it is not widely available in office-based dermatology practices (algorithm 1). PDT consists of the topical application of a photosensitizer agent (ALA or MAL) to the involved area, followed by exposure to a visible wavelength light source. (See "Photodynamic therapy".)

Standard regimens — Multiple PDT regimens have been used for the treatment of AK. Depending on the topical photosensitizer used, the incubation times, light sources, and pretreatment regimens have varied across studies, making it difficult to compare outcomes:

●Photosensitizers and light sources – A 10% ALA gel is the only PDT product approved by the US Food and Drug Administration (FDA) for both lesion- and field-directed PDT that can be used with narrowband red light illumination [39]. A 20% ALA solution is only used with blue light illuminators. However, the 10% ALA gel can also be used effectively and safely with blue light activation [40].

●Incubation time – The incubation time varies, depending on the photosensitizer formulation and the body site to be treated, and is usually determined by the treating clinician. As an example, the recommended incubation time is 3 hours for ALA gel and 14 to 18 hours for the ALA solution. An effect of the length of the incubation on treatment efficacy was illustrated in a randomized trial (n = 149) in which patients were treated with a self-adhesive ALA patch. The trial found that a four-hour incubation period was more effective for complete clearance of AKs than shorter incubation times of 30 minutes, 1 hour, or 2 hours [41].

The incubation time may affect the perceived pain intensity associated with the procedure. In an intrapatient-controlled, randomized trial designed to assess pain during the illumination phase of PDT, topical 20% ALA was applied to the entire face or scalp in 23 patients. Then, on one side, blue light was started immediately and continued for either 30, 45, or 60 minutes ("simultaneous PDT"), while on the contralateral side, blue light began one hour after ALA application and lasted 1000 seconds ("conventional PDT") [42]. All patients experienced significantly less pain during simultaneous illumination than with conventional regimen, and at three months post-treatment, lesion clearance was nearly identical on the two sides (58 and 59 percent for simultaneous and conventional PDT, respectively).

Standard and modified PDT regimens for the treatment of AKs are described in greater detail separately. (See "Photodynamic therapy", section on 'Standard photodynamic therapy regimens for actinic keratoses' and "Photodynamic therapy", section on 'Variations on the standard photodynamic therapy regimen'.)

●Adverse effects – Following PDT, a localized, erythematous reaction (similar to sunburn) can typically be expected for four to seven days and may be accompanied by a tingling or burning sensation, pain, edema, minute vesicles, or crusting. Skin exfoliation follows the inflammatory reaction for up to a week. The most common complaint during PDT is burning or stinging during light exposure; in addition, there is a small risk of producing pigmentary changes.

●Efficacy – Multiple trials and two meta-analyses have compared PDT with other therapies for AK [12-15,29,43-46]. Although data are insufficient for definitive conclusions on comparative efficacy, the cosmetic outcome from PDT appears to be superior to topical fluorouracil and cryosurgery [29,46]:

•One meta-analysis of four randomized trials (641 participants with 2170 AKs) comparing PDT with cryosurgery found that PDT had a 14 percent greater likelihood of achieving complete lesion clearance at three months than cryosurgery [46].

•In a multicenter, randomized trial (624 participants) evaluating the efficacy of topical fluorouracil, imiquimod, PDT, and ingenol mebutate, the cumulative rate of treatment success (≥75 percent reduction in the number of AKs counted at baseline) at 12 months after last treatment was 37.7 percent (95% CI 30.0-45.3) for PDT, which was inferior to topical fluorouracil (75 percent) and imiquimod (54 percent) [26]. All patients also underwent superficial curettage of their lesions prior to the topical field therapy, and patients could be retreated once if they did not achieve >75 percent clearance of lesions from baseline.

Laser-assisted photodynamic therapy — Pretreatment of the involved area with ablative and nonablative laser devices appears to increase the efficacy of PDT [47].

A meta-analysis of seven small, randomized, intraindividual trials found that laser-assisted PDT was associated with a higher likelihood of lesion clearance than PDT alone (89.5 versus 67.3 percent, respectively; relative risk 1.33, 95% CI 1.24-1.42), without a significant difference in the pain perceived by the patient [48].

Daylight photodynamic therapy — Daylight photodynamic therapy (DLPDT) using topical MAL cream 16.8% (available in Europe and Canada but not in the United States) or ALA 10% gel is an alternative to conventional PDT for the treatment of patients with multiple AKs [49,50]. Advantages of DLPDT include reduced to nearly absent pain, low cost, and ability to treat larger areas (see "Photodynamic therapy", section on 'Daylight photodynamic therapy'):

●Administration:

•DLPDT requires dry and warm weather conditions (outside temperature >10°C [>50°F]).

•A high sun protection factor (SPF) broad-spectrum sunscreen that does not contain minerals (zinc oxide and titanium dioxide also filter visible light) is applied 15 minutes before the photosensitizing cream or emulsion.

•Thirty minutes after the application of the photosensitizer, patients are sent outside for two hours.

●Efficacy – Multiple randomized trials and systematic reviews have shown that lesion clearance rates for DLPDT are similar to those seen with conventional PDT [51-55]. In an intraindividual right-left comparison study, 46 patients with a total of 453 AKs were treated with DLPDT on one side of the face or scalp, followed by conventional PDT on the other side [56]. Three months after treatment, the complete response rate was 78 percent for DLPDT versus 81 percent for conventional PDT. At 12 months, the response rate decreased to 72 and 74 percent for DLPDT and conventional PDT, respectively.

Other therapies

Topical diclofenac — Topical diclofenac 3% in hyaluronan gel is a therapeutic option for AKs [29,57,58]. Diclofenac is applied twice daily for 60 to 90 days. The most common adverse effects of diclofenac gel are dry skin, pruritus, erythema, and rash at the application site.

The use of topical diclofenac is limited by its low efficacy compared with other topical treatments and its very long treatment course [59,60]. A meta-analysis of three trials (364 patients) found that treatment with diclofenac gel resulted in complete resolution of AKs in approximately 40 percent of patients versus 12 percent with placebo [61].

Retinoids — Studies suggest that topical retinoids (adapalene, tretinoin) used daily as field therapy have little or no efficacy in reducing the number of AKs [62,63]. Low-dose oral acitretin has shown some efficacy in reducing the number of AKs and preventing nonmelanoma skin cancer in organ transplant recipients [64,65].

Field ablation treatments

Chemical peels — A chemical peel is a procedure in which a topically applied wounding agent creates smooth, rejuvenated skin by way of a wound repair process, collagen remodeling, and exfoliation. (See "Chemical peels: Procedures and complications".)

In a nonrandomized, split-face study, Jessner's solution plus 35% trichloroacetic acid (TCA) demonstrated similar efficacy and decreased rates of morbidity when compared with topical fluorouracil, with a reduction of 75 percent in the number of visible AKs for both treatments [66]. TCA 35% peel was compared with ALA-PDT for the treatment of AK in a split-area, randomized trial with 28 patients [67]. At 12 months, complete clearance was noted for 49 percent of AKs treated with TCA compared with 74 percent of those treated with ALA-PDT.

Laser resurfacing — The use of ablative laser resurfacing with carbon dioxide (CO2) and erbium:yttrium aluminum garnet (Er:YAG) lasers and nonablative fractional lasers for the treatment of AK has been reported in a few small, randomized trials and uncontrolled studies with variable results [68-72]. In one study including 24 patients with facial photodamage and AKs treated with up to four treatments with a fractionated 1927 nm nonablative thulium laser, the number of AKs was reduced by 87 percent at six months [68]. (See "Ablative laser resurfacing for skin rejuvenation".)

MULTIPLE LESIONS AND DISCRETE, HYPERTROPHIC LESIONS

Sequential therapies — Patients with multiple thin actinic keratoses (AKs) who also have discrete, hyperkeratotic lesions may benefit from the sequential use of lesion-directed and field-directed therapies (algorithm 1). For these patients, we suggest cryosurgery for the treatment of individual lesions followed by the application of fluorouracil cream to the involved area.

Examples of sequential treatments that have been evaluated in randomized trials include:

●Cryosurgery before or after topical fluorouracil [73,74]

●Cryosurgery before or after topical imiquimod [75]

●Photodynamic therapy (PDT) before or after topical fluorouracil [76,77]

●PDT before or after topical imiquimod [78,79]

The sequential use of lesion-directed therapies and field-directed therapies can optimize the clearance of visible, discrete lesions as well as subclinical lesions in photodamaged skin [3,29,80,81]. A 2019 meta-analysis of 10 randomized trials (277 patients) evaluating PDT combined with topical therapies, including imiquimod, topical fluorouracil, tazarotene, and ingenol mebutate, found that patients treated with combination therapy had a higher likelihood of complete clearance at the end of treatment (relative risk 1.63, 95% CI 1.15-2.33) [82].

Applying a topical treatment after a lesion-directed approach may reduce the potential of subclinical lesions progressing to visible AKs. Conversely, pretreating areas of AK involvement with topical agents may reveal subclinical lesions that can be treated with destructive methods, such as cryosurgery.

SPECIAL BODY SITES

Periocular area — The use of topical agents (eg, topical fluorouracil, imiquimod) is generally avoided for the treatment of actinic keratoses (AKs) on the eyelids and periorbital area due to the high risk of conjunctival injury. Cautious cryosurgery, sometimes applied with a cotton swab, may be a safer approach.

Dorsal hands/forearms/legs — AK lesions in these areas are generally thick and more treatment resistant. For AKs on the dorsum of the hands, cryosurgery followed by topical therapies (eg, topical fluorouracil, imiquimod) or photodynamic therapy (PDT) is often used [83-85]. (See 'Sequential therapies' above.)

SOLID ORGAN TRANSPLANT RECIPIENTS — Local destructive therapies, such as cryosurgery, curettage, or carbon dioxide (CO2) laser, can be used for the management of individual actinic keratoses (AKs) in solid organ transplant recipients [86]. Field-directed therapies, such as photodynamic therapy (PDT), imiquimod, and topical fluorouracil, are often preferred options for patients with numerous lesions. Because these patients often have an inadequate response to therapy, repeated treatment is often necessary. Lesions that do not respond to multiple treatments should be excised and sent for histopathologic evaluation to exclude malignancy. (See "Prevention and management of skin cancer in solid organ transplant recipients".)

Limited evidence from a small number of randomized trials favors the use of PDT over other treatment modalities in this patient population.

A 2019 systematic review of eight small, randomized trials that included 242 solid organ transplant recipients found that methyl aminolevulinate (MAL)-PDT was generally associated with a higher clearance rate compared with imiquimod 5% cream or topical fluorouracil 5% cream [87]. The complete clearance rates at three to four months after the last treatment varied across studies, ranging from 40 to 76 percent for MAL-PDT and 28 to 62 percent for imiquimod. The studies were heterogeneous and generally of poor methodologic quality.

FOLLOW-UP — Ongoing monitoring for lesion recurrence and cutaneous malignancies at 6 to 12 months post-treatment is required for all patients with a history of actinic keratoses (AKs). In a secondary analysis of a randomized trial that included 624 patients treated with 5% fluorouracil, 5% imiquimod cream, methyl aminolevulinate-photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel, the total four-year risk of developing cutaneous squamous cell carcinoma (cSCC) in a previously treated area of AK was 3.7 percent (95% CI 2.4-5.7), varying from 2.2 percent (95% CI 0.7-6.6) in patients treated with fluorouracil to 5.8 percent (95% CI 2.9-11.3) in patients treated with imiquimod [88]. (See "Cutaneous squamous cell carcinoma: Primary and secondary prevention".)

PREVENTION

Sun protection — Sun avoidance (especially during the peak hours in spring and summer), use of protective clothing, and regular use of broad-spectrum sunscreens are of key importance for the prevention of actinic keratoses (AKs). (See "Selection of sunscreen and sun-protective measures".)

The efficacy of sunscreens in reducing the development of AKs has been demonstrated by several randomized trials [89-91]. Daily sunscreen use may also decrease the risk of AK and squamous cell carcinoma (SCC) in immunosuppressed organ transplant recipients [92].

Long-term control and chemoprevention — Treatment with topical fluorouracil or imiquimod may be effective for the long-term control of AKs and prevention of cutaneous squamous cell carcinoma (cSCC) [93-95]. Chemoprevention of cSCC is discussed separately. (See "Cutaneous squamous cell carcinoma: Primary and secondary prevention", section on 'Chemoprevention'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Actinic keratosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Actinic keratosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Choice of therapy – There are multiple effective treatment options for actinic keratosis (AK), including destructive therapies (eg, cryosurgery, surgery, dermabrasion, photodynamic therapy [PDT]), topical medications (eg, topical fluorouracil, imiquimod, topical tirbanibulin, diclofenac), and field ablation treatments. The choice of therapy is influenced by several factors, including the number and distribution of lesions, patient preference and tolerance for side effects, and treatment availability and cost. Our approach to management is illustrated in the algorithm (algorithm 1). (See 'Choice of therapy' above.)

●Patients with one or few discrete, thin lesions – For patients with few isolated AKs, we suggest treatment with liquid nitrogen cryosurgery rather than other destructive treatments (Grade 2C). A freezing time of 5 to 10 seconds is usually sufficient. Cryosurgery can be quickly performed in an office-based setting, is inexpensive, does not require local anesthesia, is generally well tolerated by patients, and, in most cases, results in good or excellent cosmetic outcome. (See 'One or few discrete lesions' above and 'Hypertrophic/hyperkeratotic lesions' above.)

●Hypertrophic/hyperkeratotic lesions – For hypertrophic or hyperkeratotic lesions (picture 1), we suggest liquid nitrogen cryosurgery as the initial treatment (Grade 2C). We typically use two freeze-thaw cycles of 10 to 20 seconds, allowing time for the lesion's peripheral rim to thaw. Shave removal followed by electrodesiccation or cryosurgery to ensure hemostasis may be used for suspicious lesions requiring histopathologic examination (eg, indurated lesions, painful or ulcerated lesions, lesions recurring in <3 months). (See 'Hypertrophic/hyperkeratotic lesions' above and 'When to biopsy' above.)

●Multiple lesions/field cancerization:

•Multiple thin lesions – For patients with multiple thin lesions on the face and/or scalp, we suggest field treatment with 5% topical fluorouracil cream (Grade 2B). Alternative therapies include imiquimod, tirbanibulin, or PDT. However, based on available data, these modalities appear to be less effective. (See 'Multiple thin lesions/field cancerization' above.)

•Multiple lesions including hypertrophic/hyperkeratotic lesions – Patients with multiple AKs who also have hypertrophic or hyperkeratotic lesions (picture 1) may benefit from the sequential use of lesion-directed and field-directed therapies. For these patients, we suggest liquid nitrogen cryosurgery for the treatment of hyperkeratotic or hypertrophic lesions followed by the application of fluorouracil cream on the involved area (Grade 2C). (See 'Sequential therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph Jorizzo, MD, who contributed to an earlier version of this topic review.

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Topic 5336 Version 52.0

References

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2 : Malignant transformation of solar keratoses to squamous cell carcinoma.

3 : Current issues in the management of actinic keratosis.

4 : Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

5 : British Association of Dermatologists' guidelines for the care of patients with actinic keratosis 2017.

6 : Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses.

7 : S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

8 : Guidelines of care for the management of actinic keratosis.

9 : Healthcare utilization and management of actinic keratosis in primary and secondary care: a complementary database analysis.

10 : Cryotherapy for Actinic Keratosis: Basic Principles and Literature Review.

11 : Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis.

12 : Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study.

13 : Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study.

14 : A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.

15 : Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities.

16 : A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis.

17 : A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes.

18 : A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up.

19 : Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial.

20 : A prospective study of the use of cryosurgery for the treatment of actinic keratoses.

21 : Variables in Cryosurgery Technique Associated With Clearance of Actinic Keratosis.

22 : Management of actinic keratosis: a practical report and treatment algorithm from AKTeam™expert clinicians.

23 : Defining the actinic keratosis field: a literature review and discussion.

24 : A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Disease Severity.

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29 : Interventions for actinic keratoses.

30 : Network meta-analysis of the outcome 'participant complete clearance' in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review.

31 : Evaluation of the effectiveness of imiquimod and 5-fluorouracil for the treatment of actinic keratosis: Critical review and meta-analysis of efficacy studies.

32 : A trial-based cost-effectiveness analysis of topical 5-fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the head and neck area performed in the Netherlands.

33 : Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field-Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial.

34 : Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy.

35 : Focused update: Guidelines of care for the management of actinic keratosis.

36 : Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.

37 : Imiquimod for actinic keratosis: systematic review and meta-analysis.

38 : A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe.

39 : A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe.

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41 : Effective photodynamic therapy of actinic keratoses on the head and face with a novel, self-adhesive 5-aminolaevulinic acid patch.

42 : A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: Bilaterally controlled, randomized trial of simultaneous versus conventional illumination.

43 : A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes.

44 : Results of an investigator-initiated single-blind split-face comparison of photodynamic therapy and 5% imiquimod cream for the treatment of actinic keratoses.

45 : Intraindividual, right-left comparison of topical 5-aminolevulinic acid photodynamic therapy vs. 5% imiquimod cream for actinic keratoses on the upper extremities.

46 : Efficacy of photodynamic therapy vs other interventions in randomized clinical trials for the treatment of actinic keratoses: a systematic review and meta-analysis.

47 : Evidence-Based Clinical Practice Guidelines for Laser-Assisted Drug Delivery.

48 : Laser-assisted photodynamic therapy for actinic keratosis: A systematic review and meta-analysis.

49 : Photodynamic Therapy in Daylight for Actinic Keratoses.

50 : A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis.

51 : Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.

52 : Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe.

53 : The safety and efficacy of daylight photodynamic therapy in the treatment of actinic keratoses: a systematic review and meta-analysis.

54 : Switching From Conventional Photodynamic Therapy to Daylight Photodynamic Therapy For Actinic Keratoses: Systematic Review and Meta-analysis.

55 : Daylight versus conventional photodynamic therapy for the treatment of actinic keratosis: A meta-analysis of randomized controlled trials.

56 : Conventional vs. daylight photodynamic therapy for patients with actinic keratosis on face and scalp: 12-month follow-up results of a randomized, intra-individual comparative analysis.

57 : Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel.

58 : Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses.

59 : A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp.

60 : Open label randomized study comparing 3 months vs. 6 months treatment of actinic keratoses with 3% diclofenac in 2.5% hyaluronic acid gel: a trial of the German Dermatologic Cooperative Oncology Group.

61 : Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies.

62 : Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial.

63 : High-dose topical tretinoin for reducing multiplicity of actinic keratoses (abstract)

64 : Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans' cells in sun exposed and sun protected skin.

65 : Randomized controlled trial of acitretin versus placebo in patients at high-risk for basal cell or squamous cell carcinoma of the skin (North Central Cancer Treatment Group Study 969251).

66 : A comparison of the efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses.

67 : Randomized controlled trial comparing 35% trichloroacetic acid peel and 5-aminolaevulinic acid photodynamic therapy for treating multiple actinic keratosis.

68 : 1927-nm fractional resurfacing of facial actinic keratoses: a promising new therapeutic option.

69 : Facial resurfacing for nonmelanoma skin cancer prophylaxis.

70 : A clinical comparison and long-term follow-up of topical 5-fluorouracil versus laser resurfacing in the treatment of widespread actinic keratoses.

71 : Nonablative fractional photothermolysis for facial actinic keratoses: 6-month follow-up with histologic evaluation.

72 : Non-ablative fractional resurfacing in combination with topical tretinoin cream as a field treatment modality for multiple actinic keratosis: a pilot study and a review of other field treatment modalities.

73 : Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial.

74 : One-week treatment with 0.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double-blind, vehicle-controlled, long-term study.

75 : Efficacy of imiquimod as an adjunct to cryotherapy for actinic keratoses.

76 : A Controlled Comparison Study of Topical Fluourouracil 5% Cream Pre-Treatment of Aminolevulinic Acid/Photodynamic Therapy for Actinic Keratosis.

77 : Treatment of Actinic Keratoses: A Randomized Split-Site Approach Comparison of Sequential 5-Fluorouracil and 5-Aminolevulinic Acid Photodynamic Therapy to 5-Aminolevulinic Acid Photodynamic Monotherapy.

78 : Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream.

79 : Comparative study for the effect of photodynamic therapy, imiquimod immunotherapy and combination of both therapies on 40 lesions of actinic keratosis in Japanese patients.

80 : Impact of interval and combination therapies on the management of actinic keratosis: review and clinical considerations.

81 : The paradigm shift in treating actinic keratosis: a comprehensive strategy.

82 : Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis.

83 : An Investigator-initiated Study to Assess the Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryosurgery in the Treatment of Hypertrophic Actinic Keratosis on Dorsal Hands.

84 : Photodynamic therapy using intense pulsed light for treating actinic keratoses and photoaged skin of the dorsal hands: a randomized placebo-controlled study.

85 : Management of actinic keratosis at specific body sites in patients at high risk of carcinoma lesions: expert consensus from the AKTeam™of expert clinicians.

86 : Therapeutic options to decrease actinic keratosis and squamous cell carcinoma incidence and progression in solid organ transplant recipients: a practical approach.

87 : Local interventions for actinic keratosis in organ transplant recipients: a systematic review.

88 : Risk of Invasive Cutaneous Squamous Cell Carcinoma After Different Treatments for Actinic Keratosis: A Secondary Analysis of a Randomized Clinical Trial.

89 : High sun protection factor sunscreens in the suppression of actinic neoplasia.

90 : Reduction of solar keratoses by regular sunscreen use.

91 : A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses.

92 : Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study.

93 : Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial.

94 : 5-Fluorouracil for Actinic Keratosis Treatment and Chemoprevention: A Randomized Controlled Trial.

95 : Long-term clinical outcomes of imiquimod 5% cream vs. diclofenac 3% gel for actinic keratosis on the face or scalp: a pooled analysis of two randomized controlled trials.

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